Animals, including humans, that suffer from reagin-mediated disorders, such as atopic diseases, have a hereditary tendency to develop immediate allergic reactions involving IgE antibodies. Multiple genetic factors contribute to the expression of the resulting phenotype seen in such animals. The immediate hypersensitivity observed in atopic diseases results from exposure to specific allergens, such as the house dust mite (Dermatophagoides pteronyssinus), pollens, molds, and danders. Not surprisingly, individuals having an atopic disease are more likely to suffer from asthma, atopic dermatitis, as well as other disorders related to endogenous IgE release.
Atopic diseases such as allergic dermatitis, asthma, and the like, also occur in the canine species, including in domestic dogs. Such dogs generally begin to show signs of atopy between one and three years of age. Due to the hereditary nature of the disease, several breeds, including golden retrievers, most terriers, Irish sellers, Lhasa apsos, Dalmatians, bulldogs and Old English sheep dogs have a greater tendency to be atopic, though other types of dogs, including mixed breeds, also are known to suffer from this condition. The incidence of at least one particular type of atopy, atopic dermatitis, is increasing significantly in both humans and canines alike.
Atopic canines will usually rub, lick, chew, bite or scratch at their feet, muzzle, ears, armpits or groin area, resulting in hair loss, reddening, and thickening of the skin. In some cases several skin conditions combine to cause an animal to itch when a single allergy alone would not have resulted in such itching. These aggravating problems can be due to air borne-allergens (pollens, etc.), allergens in food, and allergens from parasites (fleas, etc.). Bacterial and/or yeast infections of the skin also can augment the itching sensation.
One simple means of alleviating the annoying symptoms of atopy is to avoid the inciting allergen(s). Unfortunately, such avoidance is generally impractical. Heretofore, veterinary practitioners have treated canine atopic dermatitis by administering oral antihistamines, oral or topical corticosteroid anti-inflammatory agents, other immune system suppressants, such as cyclosporine or tacrolimus, fatty acid supplements, and allergen specific immunotherapy (which requires injection of the identified antigen). However, none of these treatments work in all cases. Moreover, such treatments are costly and/or give rise to significant side effects. Thus, there is a longstanding need for safer, more effective and more economical approaches to treating or suppressing the symptoms of canine atopic dermatitis.
The mammalian immune response is based on a series of complex cellular interactions, called the “immune network”. Much of the immune response revolves around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, with soluble proteins called cytokines playing a critical role in mediating/controlling/regulating these cellular interactions. Thus, cytokines and immune cells serve to mediate specific physiological mechanisms or pathways leading to the various inflammatory disorders.
Allergic inflammation is the result of a complex immunological cascade which leads T cells to produce dysregulated TH2-derived cytokines such as IL-4, IL-5, and IL-13. These cytokines, in turn, trigger bronchial hyperreactivity, IgE production, eosinophilia, and mucus production (see, e.g., Busse and Lemanske, Jr. (2001) N. Engl. J. Med. 344:350-62; Holgate (2000) Br. Med. J. 320:231-234); and Renauld (2001) J. Clin. Pathol. 54:577-589).
Thymic Stromal Lymphopoietin protein (TSLP) is an IL-7-like cytokine that was initially identified in mice as a factor that supported: (i) the in vitro development of surface IgM+ B cells, and (ii) B and T cell proliferation (Friend et al., 1994 Exp Hematology 22:321-328, see also, Levin et al., 1999, J. Immunol 162: 677-683), TSLP is now known to bind a cellular receptor comprising IL-7R-alpha subunit and a unique receptor subunit called TSLP-R. This interaction triggers signal transduction via STAT activation or Thymus and Activation-Regulated Chemokine (TARC) expression in a hematopoietic cell, such as a myeloid lineage cell such as a monocyte, or a dendritic cell. (see, e.g., co-owned U.S. Pat. No. 6,890,734, incorporated herein by reference).
TSLP also may play a significant role in mice in the pathogenesis of allergic diseases such as atopic dermatitis and asthma. For example, transgenic mice in which the expression of TSLP gene was specifically induced in the skin show immunological and clinical features of atopic dermatitis such as eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing skin homing receptors, and elevated serum levels of IgE. Moreover, lungs of mice expressing a lung-specific TSLP transgene show immunological and clinical features of asthma including massive infiltration of leukocytes, goblet cell hyperplasia, sub-epithelial fibrosis, an increase in T helper type 2 cytokines, and increased levels of IgE.
Sims et al. obtained the cDNA sequence of murine TSLP employing expression cloning, but were unable to clone the human homologue with hybridization probes based on the murine TSLP (Sims et al. 2000, J exp Med, 192: 671-680). Subsequently, the human homologue was identified through detailed EST analysis. The human TSLP nucleotide sequence was found to have only 43% homology with the corresponding mouse sequence.
Therefore, there remains a need to provide new and more practical treatments for atopic disorders in canines, including atopic dermatitis and its associated clinical manifestations. Moreover, there is a need to isolate factors that are involved in the immunological cascade that leads to atopic disorders in canines that could lead to the development of such treatments.
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